Analysis of stem-cell associated genes in breast cancer as biomarkers and predictors of cancer malignancy – Dr Adrienne Edkins
Prof Adrienne Edkins
Title of the project
Analysis of stem-cell associated genes in breast cancer as biomarkers and predictors of cancer malignancy.
The aim of this project is to conduct a novel fundamental study to support two clinical needs for breast cancer. These are: (1) the identification of new diagnostic or prognostic markers that correlate with clinical outcome and can therefore be utilized to inform treatment; and (2) the development of more effective treatments against novel targets, particularly in the case of aggressive and metastatic tumours that are over-represented in African communities (such as triple negative breast tumours).
Breast cancer is the most common cancer in women. While there have been advances in breast cancer treatment through the development of new drugs, in most cases, particularly for aggressive or advanced breast cancer, there are few effective treatments. In many cases, early diagnosis and classification of tumours can aid significantly in treatment and cure. One effective way of categorizing breast cancer is to compare the levels of different genes between tumours in order to identify what is known as a ‘genetic expression signature’. If this genetic expression signature can be correlated with the biological responses of the different tumours, it may have prognostic or diagnostic value. This means it may be useful in identifying tumours that may be drug resistant or more aggressive, and therefore support treatment choices. Recent research has suggested that breast cancers, along with other cancers, may develop from a rare population of cancer cells that are biologically different from the majority of the tumour cells. These cancer-initiating cells, known as cancer stem cells, are defined by having stem cell-like characteristics. Stem cells are early undifferentiated cells that are able to divide and differentiate into the range cells of the body. In a similar analogy, cancer stem cells are considered as those cells that can initiate tumour formation, as well as divide and differentiate into all the cells contained within a cancer. This cancer stem cell theory can neatly explain why many cancers are heterogeneous, yet are derived from a single ancestor cell. The cancer stem cell theory further suggests that those cancers associated with stem cell-like characteristics are more aggressive, difficult to treat and more likely to spread. It should therefore be theoretically possible to examine the levels of stem cell associated genes in different breast cancers, to obtain an indication of the response that that cancer will have to treatment, or the likelihood that it will spread and develop a secondary metastasis. Certain types of breast cancer are more likely to be linked with stem cell characteristics. In particular, a highly aggressive and difficult to treat breast cancer, known as the triple negative subtype, has been associated with a high propensity for stem cell characteristics. Interestingly, Southern African women appear predisposed to this triple negative breast cancer, for reasons that are not completely understood. Some studies have been conducted in African American women, but we have little molecular information on the link between stem cell characteristics and breast cancers from indigenous South African populations. Much of what we know about cancers in African populations is derived from studies in African American women, who may share a genetic heritage with Southern African women, but are exposed to substantially different environmental factors.
During our study we will evaluate whether there is a correlation between stem cell characteristics and breast cancer biology. Using cell line models and clinical samples we will evaluate whether the gene profiles we generate might be useful in diagnosis of breast cancer subtypes or clinical outcome, or might inform particular treatment strategies. We will focus on the triple negative breast cancer subtype and will generate population specific data that will aim to enhance our understanding of why indigenous Southern African women are more predisposed to this type of breast cancer. Through this study, we hope to determine whether the cancer stem cell theory of cancer development is relevant in the South African context and to identify new targets for future therapeutic intervention.
Our research is focused on analyzing the relationship between marker genes of stem cells and cancer characteristics in an aggressive and difficult to treat subtype of breast cancer. Our previous research identified OCT4 as a possible candidate gene for regulating the aggressive nature of breast tumours. We characterized a number of breast cancer cell lines for the levels of OCT4 and then correlated these with a number of biological features that are representative of the degree of malignancy of the cells. These analyses included measures of the growth, migration and invasion of the cells. We then compared the level of OCT4 to the biological characteristics of our cells. We determined that those cells that had naturally high levels of OCT4 also showed a high propensity for cell growth, suggesting that the two features may be linked. We did not observe such a correlation between OCT4 levels and other features like cell migration or invasion. However, a correlation between two characteristics does not mean that they exhibit a causal relationship. In order to confirm whether or not there is a direct relationship between OCT4 levels and cell growth, we artificially introduced high levels of OCT4 into a normal cell line and observed the expected increase in cell growth. This suggests to us that high OCT4 levels are required for cell proliferation and that increasing the OCT4 level in a cell is sufficient to increase the growth rate of that cell. We next aim to conduct the opposite experiment, where we will deplete the levels of OCT4 in a cell line that has naturally high levels of the protein. We anticipate that, if OCT4 and growth are related, we will observe a decrease in the growth rate of these cells. We are currently conducting these experiments in both breast cancer and a model cell line.